The polyploid state plays a tumor suppressive role in the liver
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA428085 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6432960.fastq.gz | Fastqsanger.gz | |||
| SRR6432970.fastq.gz | Fastqsanger.gz | |||
| SRR6432980.fastq.gz | Fastqsanger.gz | |||
| SRR6432990.fastq.gz | Fastqsanger.gz | |||
| SRR6433000.fastq.gz | Fastqsanger.gz |
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Project description:Most cells in the liver are polyploid, but the functional role of polyploidy is unknown. We developed orthogonal mouse models to transiently and potently alter liver ploidy. Premature weaning, as well as knockdown of E2f8 or Anln, allowed us to toggle between diploid and polyploid states. While there was no impact of ploidy alterations on liver function, metabolism, or regeneration, more polyploid mice suppressed and more diploid mice accelerated tumorigenesis in mutagen and high-fat induced models. Mechanistically, the diploid state was more susceptible to Cas9-mediated tumor suppressor loss but was similarly susceptible to MYC oncogene activation, indicating that ploidy differentially protected the liver from distinct genomic aberrations.
2019-01-01 | GSE108645 | GEO
Project description:Most cells in the liver are polyploid, but the functional role of polyploidy is unknown. Polyploidization occurs through cytokinesis failure and endoreduplication around the time of weaning. To interrogate polyploidy while avoiding irreversible manipulations of essential cell-cycle genes, we developed orthogonal mouse models to transiently and potently alter liver ploidy. Premature weaning, as well as knockdown of E2f8 or Anln, allowed us to toggle between diploid and polyploid states. While there was no detectable impact of ploidy alterations on liver function, metabolism, or regeneration, mice with more polyploid hepatocytes suppressed tumorigenesis and mice with more diploid hepatocytes accelerated tumorigenesis in mutagen- and high-fat-induced models. Mechanistically, the diploid state was more susceptible to Cas9-mediated tumor-suppressor loss but was similarly susceptible to MYC oncogene activation, indicating that polyploidy differentially protected the liver from distinct genomic aberrations. This suggests that polyploidy evolved in part to prevent malignant outcomes of liver injury.
| S-EPMC5828993 | biostudies-literature
Project description:BACKGROUND & AIMS: Thirty to ninety percent of hepatocytes contain whole genome duplications, making it imperative to understand the fates and functions of these polyploid cells and how they affect development of liver disease. An important question is how polyploid cells respond to chronic proliferative demands, which are characteristic of liver diseases, but a challenging situation for cells with multiple genomes. METHODS: To interrogate liver polyploidy, we employed a mouse with reversible ANLN ( Anillin actin binding protein) knockdown that drives hepatocyte polyploidization in a doxycycline inducible fashion. Diethylnitrosamine (DEN) and carbon tetrachloride (CCl4) were used to induce chronic liver damage and hepatocellular carcinoma (HCC). We performed partial hepatectomies to test regeneration and RNA-seq to assess gene expression changes. Lineage tracing was used to rule out repopulation from non-hepatocyte sources. In vivo imaging of mitotic hepatocytes estimated the frequency of aneuploidy during regeneration, and exome sequencing of 54 human cirrhotic nodules was used to quantify aneuploidy. RESULTS: Hepatocytes from mice given chronic CCl4 alone showed significant increases in ploidy. Super-polyploid mice with 97% polyploid hepatocytes, due to induced knockdown of Anln , were almost completely protected from tumorigenesis induced by DEN and chronic CCl4 . The protection was not associated with differences in regenerative capacity, tissue fitness, gene regulation, or mitotic errors. Regenerative contributions from a non-hepatocyte population were ruled out using lineage tracing, confirming that polyploids can replenish tissues during chronic damage. No lagging chromosomes or micronuclei were found in mitotic polyploid cells and there was no evidence of chromosomal copy number variations in 54 nodules, suggesting that aneuploidy is not a common outcome of polyploid cell divisions. CONCLUSION: During chronic injury, polyploid hepatocytes readily divide and regenerate while being buffered from tumor suppressor loss and tumorigenesis. Therapeutic strategies to increase numbers of polypoid hepatocytes could prevent cancer while preserving regeneration.
2020-02-12 | GSE145084 | GEO
Project description:To examine gene expression changes duging aging in polyploid and diploid hepatocytes, diploid and polyploid hepatocytes were sorted from young and aged multi-reporter mice and their gene expressions were analyzed by high-throughput RNA sequence.
2021-04-14 | GSE161171 | GEO
Project description:TGFß in the microenvironment induces a physiologically occurring immune-suppressive senescent state
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Project description:Treatment of PC3 and MDA-MB-231 cell lines with sublethal doses of docetaxel or cisplatin in vitro resulted in induction of polyploid cancer cells. Single cell copy RNA-sequencing was conducted to understand resistance of polyploid cancer cells to chemotherapy.
2024-09-13 | GSE270568 | GEO
Project description:Treatment of PC3 and MDA-MB-231 cell lines with sublethal doses of docetaxel or cisplatin in vitro resulted in induction of polyploid cancer cells. Single cell copy number profiling was conducted to understand resistance of polyploid cancer cells to chemotherapy.
2024-09-13 | GSE270567 | GEO
Project description:Glis3 plays a crucial role in spermatogenesis
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Project description:The polyploid S. cerevisiae karyotypes were analyzed by array-CGH to identify the deletion or duplication of gene or chromosome during the strain construction and after experimental evolution.
2016-10-11 | GSE76595 | GEO
Project description:The liver contains a mixture of hepatocytes with diploid or polyploid (tetraploid, octaploid, etc.) nuclear content. Polyploid hepatocytes are commonly found in adult mammals, representing ~90% of the entire hepatic pool in rodents. The cellular and molecular mechanisms that regulate polyploidization have been well characterized; however, it is unclear whether diploid and polyploid hepatocytes function similarly in multiple contexts. Answering this question has been challenging because proliferating hepatocytes can increase or decrease ploidy, and animal models with healthy diploid-only livers have not been available. Mice lacking E2f7 and E2f8 in the liver (liver-specific E2f7/E2f8 knockout; LKO) were recently reported to have a polyploidization defect, but were otherwise healthy. Herein, livers from LKO mice were rigorously characterized, demonstrating a 20-fold increase in diploid hepatocytes and maintenance of the diploid state even after extensive proliferation. Livers from LKO mice maintained normal function, but became highly tumorigenic when challenged with tumor-promoting stimuli, suggesting that tumors in LKO mice were driven, at least in part, by diploid hepatocytes capable of rapid proliferation. Indeed, hepatocytes from LKO mice proliferate faster and out-compete control hepatocytes, especially in competitive repopulation studies. In addition, diploid or polyploid hepatocytes from wild-type (WT) mice were examined to eliminate potentially confounding effects associated with E2f7/E2f8 deficiency. WT diploid cells also showed a proliferative advantage, entering and progressing through the cell cycle faster than polyploid cells, both in vitro and during liver regeneration (LR). Diploid and polyploid hepatocytes responded similarly to hepatic mitogens, indicating that proliferation kinetics are unrelated to differential response to growth stimuli. Conclusion: Diploid hepatocytes proliferate faster than polyploids, suggesting that the polyploid state functions as a growth suppressor to restrict proliferation by the majority of hepatocytes.
| S-EPMC6532408 | biostudies-literature